Complex Distribution, Not Absolute Amount of Adiponectin, Correlates with Thiazolidinedione-mediated Improvement in Insulin Sensitivity

Utpal B. Pajvani, Meredith A. Hawkins, Terry P. Combs, Michael W. Rajala, Tom Doebber, Joel P. Berger, John A. Wagner, Margaret Wu, Annemie Knopps, Anny H. Xiang, Kristina M. Utzschneider, Steven E. Kahn, Jerrold M. Olefsky, Thomas A. Buchanan, Philipp E. Scherer

Research output: Contribution to journalArticle

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Abstract

Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates β oxidation in muscle. Here, we show that the ratio, and not the absolute amounts, between these two oligomeric forms (HMW to LMW) is critical in determining insulin sensitivity. We define a new index, SA, that can be calculated as the ratio of HMW/(HMW + LMW). db/db mice, despite similar total adiponectin levels, display decreased SA values compared with wild type littermates, as do type II diabetic patients compared with insulin-sensitive individuals. Furthermore, SA improves with peroxisome proliferator-activated receptor-γ agonist treatment (thiazolidinedione; TZD) in mice and humans. We demonstrate that changes in SA in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in SA (ΔSA) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein. These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner.

Original languageEnglish (US)
Pages (from-to)12152-12162
Number of pages11
JournalJournal of Biological Chemistry
Volume279
Issue number13
DOIs
StatePublished - Mar 26 2004

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Adiponectin
Insulin Resistance
Molecular Weight
Molecular weight
Insulin
Proteins
Muscle
Liver
Serum
Muscles
Peroxisome Proliferator-Activated Receptors
Gluconeogenesis
2,4-thiazolidinedione
Clamping devices
Adipocytes
Blood Proteins
Therapeutics
Display devices
Glucose
Oxidation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Complex Distribution, Not Absolute Amount of Adiponectin, Correlates with Thiazolidinedione-mediated Improvement in Insulin Sensitivity. / Pajvani, Utpal B.; Hawkins, Meredith A.; Combs, Terry P.; Rajala, Michael W.; Doebber, Tom; Berger, Joel P.; Wagner, John A.; Wu, Margaret; Knopps, Annemie; Xiang, Anny H.; Utzschneider, Kristina M.; Kahn, Steven E.; Olefsky, Jerrold M.; Buchanan, Thomas A.; Scherer, Philipp E.

In: Journal of Biological Chemistry, Vol. 279, No. 13, 26.03.2004, p. 12152-12162.

Research output: Contribution to journalArticle

Pajvani, UB, Hawkins, MA, Combs, TP, Rajala, MW, Doebber, T, Berger, JP, Wagner, JA, Wu, M, Knopps, A, Xiang, AH, Utzschneider, KM, Kahn, SE, Olefsky, JM, Buchanan, TA & Scherer, PE 2004, 'Complex Distribution, Not Absolute Amount of Adiponectin, Correlates with Thiazolidinedione-mediated Improvement in Insulin Sensitivity', Journal of Biological Chemistry, vol. 279, no. 13, pp. 12152-12162. https://doi.org/10.1074/jbc.M311113200
Pajvani, Utpal B. ; Hawkins, Meredith A. ; Combs, Terry P. ; Rajala, Michael W. ; Doebber, Tom ; Berger, Joel P. ; Wagner, John A. ; Wu, Margaret ; Knopps, Annemie ; Xiang, Anny H. ; Utzschneider, Kristina M. ; Kahn, Steven E. ; Olefsky, Jerrold M. ; Buchanan, Thomas A. ; Scherer, Philipp E. / Complex Distribution, Not Absolute Amount of Adiponectin, Correlates with Thiazolidinedione-mediated Improvement in Insulin Sensitivity. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 13. pp. 12152-12162.
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AU - Rajala, Michael W.

AU - Doebber, Tom

AU - Berger, Joel P.

AU - Wagner, John A.

AU - Wu, Margaret

AU - Knopps, Annemie

AU - Xiang, Anny H.

AU - Utzschneider, Kristina M.

AU - Kahn, Steven E.

AU - Olefsky, Jerrold M.

AU - Buchanan, Thomas A.

AU - Scherer, Philipp E.

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N2 - Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates β oxidation in muscle. Here, we show that the ratio, and not the absolute amounts, between these two oligomeric forms (HMW to LMW) is critical in determining insulin sensitivity. We define a new index, SA, that can be calculated as the ratio of HMW/(HMW + LMW). db/db mice, despite similar total adiponectin levels, display decreased SA values compared with wild type littermates, as do type II diabetic patients compared with insulin-sensitive individuals. Furthermore, SA improves with peroxisome proliferator-activated receptor-γ agonist treatment (thiazolidinedione; TZD) in mice and humans. We demonstrate that changes in SA in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in SA (ΔSA) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein. These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner.

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